tbuckley/cabot-search huggingface dataset:
Abstract 12499: Anomalous Coronary Arteries Are Associated With Ischemia in the Ischemia Trial
Authors: Vita Jaspan, Jonathon A Leipsic, Hayley Nemeth, G B Mancini, Matthew Budoff, Cameron Hague, James Min, Leslee J Shaw, Daniel Berman, Michael Picard, Bernard R Chaitman, Raymond Y Kwong, Sean OBrien, Judith S Hochman, David J Maron, Harmony Reynolds
Journal: Circulation (2022)

Introduction: Coronary anomalies are detected in 0.3-2.3% of patients undergoing coronary computed tomography angiography (CCTA). Data are scarce on atherosclerosis severity in anomalous arteries and relationship to ischemia on stress testing. Hypothesis: High risk features of anomalous coronary arteries are associated with ischemia, even in the absence of coronary stenosis on CCTA. Methods: 5,903 participants enrolled in the ISCHEMIA trial program with site-determined moderate or severe ischemia underwent CCTA. A core laboratory assessed atherosclerosis severity and made note of anomalous coronary origin. A single reader at the CCTA core laboratory re-evaluated all identified anomalies to assess high risk features and origin, blinded to stress test results. Patients were excluded if stress test results were unavailable. We assessed the relationship between type of anomaly and vessel with ischemia in the subtended territory on stress imaging, and stenosis severity. Results: There was anomalous origin of a coronary artery in 56 of 5,903 CCTA cases (0.9%). Age, sex and CAD risk factors were similar between patients with vs. without anomalies. Anomalous origin affected the left circumflex (LCX) in 28, right coronary artery (RCA) in 21, left main (LM) in 4, and left anterior descending (LAD) in 3. Ischemia was severe on stress testing in 58.2%, moderate in 34.5%, mild in 3.6% and absent in 3.6%. High risk anomalies were present in 17/56 (30.3%, 16/21 RCA and 1/4 LM), including inter-arterial course in 28.6%, intra-mural course in 1.8%, and slit-like orifice in 12.5%. Most anomalous coronaries (82.9%) were associated with ischemia in the subtended territory. Among anomalies associated with ischemia, 37.9% had &lt;50% stenosis and 62.1% had &lt;70% stenosis (Figure). Of those with &lt;70% stenosis, 27.6% had high risk features. Conclusions: Anomalous coronary arteries in stable patients are associated with ischemia, even in the absence of severe atherosclerotic disease.
Abstract 12329: Checkpoint Kinase 1 Protein Therapy Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair in a Porcine Model of Myocardial Ischemia/Reperfusion Injury
Authors: tianwen wei, TianKai Shan, Hao Wang, tongtong yang, jiawen chen, Liansheng Wang
Journal: Circulation (2022)

Objective: To investigate the impact of recombinant human checkpoint kinase 1 (rhCHK1) on cardiomyocyte renewal and myocardial repair after myocardial ischemia/reperfusion (I/R) injury in swine. Methods: Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis using iGPS algorithm revealed CHK1 kinase with enriched substrates and upregulated phosphorylation levels. Swine myocardial ischemia/reperfusion injury was induced by ligating the left anterior descending coronary artery for 60 minutes, and followed by reperfusion. Immediately after reperfusion, rhCHK1 protein (1mg/kg) dissolved in hydrogel or equivalent hydrogel was injected into the infarcted border zone. The therapeutic efficacy of rhCHK1 post I/R injury was evaluated by ECG, echocardiography, MRI, hematological indices and immunofluorescence. Results: Intramyocardial injection of rhCHK1-hydrogel efficiently delivered rhCHK1 to the cardiomyocytes surrounding the infarcted area of pig hearts without affecting other organs. A single administration of rhCHK1 protein (1mg/kg) prominently stimulated cardiomyocytes proliferation, reduced cardiac inflammation and improved vascularity 3 days after I/R. At 28-days post rhCHK1-hydrogel therapy, improved cardiac function, reduced infarct size and cardiac scar area, and attenuated ventricular remodeling were evidenced in I/R swine. Mechanistically, rhCHK1 stimulated CMs renewal and cardiac repair by activating mTOR/CTHRC1/P70S6K signaling pathways. Conclusion: Our study demonstrates that myocardial injection of rhCHK1 could promote cardiomyocyte proliferation, inhibit local myocardial inflammation and promote angiogenesis to facilitate myocardial repair and cardiac function after I/R injury in adult pigs through activating mTOR/CTHRC1/P70S6K signaling pathways.
Abstract 11959: Cardiopulmonary Exercise Testing Delineates Multiple Contributing Factors to Poor Exercise Performance in Childhood Cancer Survivors
Authors: Takeshi Tsuda, Gina D Aloisio, Joanne Quillen
Journal: Circulation (2022)

Background: Childhood cancer survivors (CCS) show decreased exercise performance despite normal ventricular function at rest. Multiple underlying mechanisms are considered. Methods: Cardiopulmonary exercise testing (CPET) was performed in asymptomatic off-treatment CCS. Patients were divided into four groups by their peak oxygen consumption (pVO2) at 35 and 25 ml/kg/min in males and females, respectively (“Good” and “Poor” performance groups). * denotes weight-indexed values. Data are shown as mean ± standard deviation. Results: Demographic and CPET data are presented in Table 1. There was no notable correlation between total anthracycline dosage and CPET values. Weight, body mass index, and peak respiratory exchange ratio were significantly higher in “Poor” groups in both sexes. Peak oxygen pulse (pOP*) and ventilatory anaerobic threshold (VAT*) were significantly lower whereas heart rate (HR) dependency on work rate (WR*) (= ΔHR/ΔWR*) was significantly higher in “Poor” groups than in “Good” groups. There was no difference in ventilatory efficiency presented as a slope of ventilation (VE)/carbon dioxide output (VCO2)(ΔVE/ΔVCO2). Figure 1 demonstrated the relationship between weight and pVO2 (L/min) and between ΔHR/ΔWR* and pOP*, showing distinct difference between “Good” and “Poor” performers in both sexes; “Poor” performers revealed lower skeletal mass and stroke volume effects. Conclusions: Treatment-mediated cardiotoxicity is not the only cause of poor exercise performance in CCS. In addition to limited stroke volume indicated by lower pOP* with higher HR dependency, skeletal muscle loss and increased BMI mitigated the overall exercise performance.
Abstract 11958: Incidence of Acute Thrombotic Occlusion and Its Predictors After Contemporary Femoropopliteal Endovascular Therapy in Patients With Peripheral Artery Disease
Authors: SHO NAKAO, Osamu Iida, Mitsutoshi Asai, masaharu masuda, Shin Okamoto, Takayuki Ishihara, Kiyonori Nanto, Takuya Tsujimura, Yasuhiro Matsuda, Yosuke Hata, Hiroyuki Uematsu, Taku Toyoshima, Naoko Higashino, Toshiaki Mano
Journal: Circulation (2022)

Introduction: Although there is robust evidence for the superiority of contemporary femoropopliteal (FP)-specific devices to traditional therapy using non-coated balloon or bare metal stent, cohesive reports on the incidence of acute thrombotic occlusion (ATO) after endovascular therapy (EVT) with contemporary FP devices are scarce. This study investigated the incidence of ATO and its predictors after contemporary FP-EVT for peripheral artery disease. Methods: We retrospectively examined 763 limbs (chronic limb-threatening ischemia [CLTI]: 44%, involving popliteal arterial lesion: 44%) in 644 patients (mean age: 75±9 years, male: 71%, hemodialysis: 34%) who successfully underwent EVT with contemporary FP devices (drug-coated balloon [DCB]: n=235, scaffold: n=528 [drug-coated stent: n=220, stent graft: n=158, drug-eluting stent: n=150]) from June 2012 to July 2020. The outcome measure was ATO defined as acute onset of claudication and/or signs of CLTI in combination with angiographic evidence of occlusive thrombus formation within the treated segment. Cox proportional hazards regression models were used to identify baseline characteristics associated with the incidence of ATO after contemporary FP-EVT. Results: The 24-month incidence of ATO in the overall population was 4.3±0.8% (DCB: 1.0±0.7% versus scaffold: 5.8±1.1%, P&lt;.01). Due to the remarkably lower incidence of ATO after EVT with DCB, risk factors for ATO in patients treated with scaffold was identified. Hemodialysis (hazard ratio [HR]: 2.63, P=.02) and involving popliteal lesion (HR: 8.22, P&lt;.01) were independently associated with an increased risk of ATO. The 24-month incidence of ATO in patients with those risk factors was 21.0±3.3%, while that in patients without those factors was 0.5±0.2%. Conclusions: We found a substantial incidence of ATO after contemporary FP-EVT, particularly with scaffold. Hemodialysis and involving popliteal lesion were significantly associated with ATO risk in patients treated with scaffold. The scaffold was safely used in patients without those risk factors of ATO, but a non-scaffolding strategy, including surgical bypass therapy, should be considered for patients with those risk factors.
Abstract 11734: Myocardial Perfusion Reserve Quantified by Stress Cardiovascular Magnetic Resonance Imaging is Reduced in Long COVID Patients Presenting With Chest Pain
Authors: Austin Culver, Peter Ju, Daniel Kim, Brandon Benefield, Li-Yueh Hsu, Suvai Gunasekaran, Michael Ison, Ravi Kalhan, Bradley D Allen, Michael Markl, Clyde Yancy, Daniel C Lee
Journal: Circulation (2022)

Introduction: Chest pain is common in patients with Post-acute Sequelae of SARS-CoV-2 (PASC), also known as long COVID, but the mechanism is unknown. Hypothesis: We hypothesized that PASC patients with chest pain have impaired myocardial perfusion reserve (MPR) measured by stress perfusion cardiovascular magnetic resonance (CMR) imaging. Methods: We retrospectively identified the first 30 consecutive patients who underwent clinically ordered adenosine stress perfusion CMR for chest pain persisting &gt;4 weeks after SARS-CoV-2 infection (PASC). Patients with a history of coronary artery disease (CAD) or left ventricular ejection fraction (LVEF) &lt;50% were excluded. Patients without a history of SARS-CoV-2 infection who had a normal clinically ordered perfusion CMR served as controls. A previously-described automated pixel-wise quantitative perfusion tool was used to calculate stress and rest myocardial blood flow (MBF) in mL/min/g, and MPR as the ratio of stress MBF/rest MBF. The cutoff for reduced MPR was &gt;2 SD below mean MPR for controls. Results: In 30 PASC (67% female, age 43±13) and 13 controls (54% female, age 50±12), with LVEF (61±6% vs 59±8%), native T1 (1001±49 vs 992±57 ms), T2 (49.5±3.7 vs 48.0±3.3 ms), and ECV (24.6±2.9 vs 24.6±2.6%) were similar (p&gt;0.2 for all). Prior pericarditis (n=2) or prior myocarditis (n=3) were infrequent, with no acute disease by CMR. PASC patients had significantly lower global MPR than controls (1.54±0.25 vs. 2.20±0.36, p&lt;0.001), and 16/30 (53%) PASC patients had reduced MPR (&lt;1.49). Clinical ischemia evaluation revealed obstructive CAD in only 2 PASC patients. Conclusions: In PASC patients with chest pain undergoing stress perfusion CMR, global MPR is frequently reduced and is significantly lower than in patients with normal clinical perfusion CMR and no history of SARS-CoV-2 infection. This study raises the possibility that microvascular dysfunction is an important cause of chest pain in patients with long COVID.
Abstract 12398: CD151 Expression Reflects Different Features in Cardiac Subtype Specification From Human Pluripotent Stem Cells
Authors: Misato Koakutsu, Kenji Miki, Yuki Naka, Masako Sasaki, Chikako Okubo, Megumi Narita, Kenichi Imahashi, Yoshinori Yoshida
Journal: Circulation (2022)

Introduction: In conventional cardiac differentiation methods, a heterogeneous cardiac population is generated from human induced pluripotent stem cells (hiPSCs). Purifying ventricular- or atrial cardiomyocytes (VCMs or ACMs, respectably) is valuable for drug discovery for region-specific heart diseases. Previously, we have identified a novel marker, CD151, which can separate advanced specified subtypes; CD151 high VCMs in ventricular inducing condition (VIC) and CD151 low ACMs in atrial inducing condition (AIC). Although CD151 is known as a cell adhesion molecule, the function in cardiac subtype specification is unclear. In this study, we addressed the mechanisms of how CD151 distinguishes cardiomyocyte subtypes in cardiac differentiation from hiPSCs. Methods: We performed RNA sequencing in VIC- and AIC- CD151 high/low CMs. Pathway analysis using differential expression genes between CD151 high/low CMs was conducted to identify prominent pathways in subtype specification. Results: In VIC, mitosis-related genes were enriched in CD151 high VCMs. To clarify whether those genes affect cell proliferation or multi-nucleation, we performed the flow cytometric analysis of CD151 high/low VCMs with KI-67 proliferation marker and Hoechst staining. Although the percentage of KI67-positive cells was almost the same, binucleated cells were significantly more in CD151 high VCMs than in CD151 low VCMs. In AIC, transcriptome analysis suggested that Notch signaling was activated in CD151 high ACMs. To reveal that Notch signaling inhibits atrial specification, we analyzed ACMs treated with LY411575, a Notch signaling inhibitor. LY411575 induced atrial marker gene expression and increased the number of cells showing action potentials of ACMs. CD151 low ACMs after LY411575 treatment contained ACMs with the highest efficiency. Conclusion: Our results demonstrate that the CD151 expression indicates mitotic activity in VCMs. CD151 high VCMs are more advanced specified VCMs with binucleation without cell proliferation. On the other hand, in ACMs, CD151 works as an indicator of Notch signaling, which suppresses atrial specification. Our study provides a novel approach to generating and purifying hiPSCs-ACMs by Notch inhibition and CD151 separation.
Abstract 11203: Blood Metabolomes as Non-Invasive Biomarkers and Targets of Metabolic Interventions for Doxorubicin- and Trastuzumab-Induced Heart Failure
Authors: Chanisa Thonusin, Wichwara Nawara, Thawatchai Khuanjing, Nanthip Prathumsap, Apiwan Arinno, Benjamin Ongnok, Busarin Arunsak, Sirawit Sriwichaiin, Siriporn Chattipakorn, Nipon Chattipakorn
Journal: Circulation (2022)

Introduction: Cardiac metabolic impairment is a critical component of heart failure pathophysiology. However, our understanding on the blood metabolomics and their potential as non-invasive metabolic biomarkers in doxorubicin- and trastuzumab-induced heart failure remains limited. In this study, we identified the changes in blood metabolome levels as well as their associations with cardiac dysfunction and cardiac injury in rats with doxorubicin- and trastuzumab-induced cardiotoxicity. Methods: 8-week-old male Wistar rats were divided into 4 groups (n=6/group) to receive intraperitoneal injection with either 1) 3 mg/kg/day of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin), 2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group), 3) 4 mg/kg/day of NSS at days 0-6 (control group for trastuzumab), and 4) 4 mg/kg/day of trastuzumab at days 0-6 (trastuzumab group). Four days after the last injected dose, cardiac function was evaluated. The rats were then sacrificed to collect blood and heart for the quantitation of 107 serum and 100 cardiac metabolome levels, respectively, using mass spectrometry-based targeted metabolomics. Results: Strong relationships between 72 and 61 cardiac versus serum metabolomes were found in doxorubicin and trastuzumab groups, respectively. Correlations between cardiac function and cardiac injury versus 28 and 58 serum metabolomes were also shown in doxorubicin and trastuzumab groups, respectively. Importantly, patterns of metabolome change were different between doxorubicin and trastuzumab groups (Figure). Conclusions: Our findings highlight the potential role of blood metabolomes as non-invasive biomarkers to assess the severity and prognosis of doxorubicin- and trastuzumab-induced heart failure. These findings could lead to the development of metabolic targeted therapy specific for the cardioprotection during different phases of cancer treatment.
Abstract 11928: Effect of Hospitalizations on Benefits From Exercise Interventions in Peripheral Artery Disease: Results From LITE Randomized Clinical Trial
Authors: Neela D Thangada, Shujun Xu, Lu Tian, Lihui Zhao, Mary M McDermott
Journal: Circulation (2022)

Background: Walking exercise is first line therapy for lower extremity peripheral artery disease (PAD); however, hospitalizations during therapy are common. In post-hoc analyses, we evaluated the effect of hospitalizations on benefits from the exercise interventions in the LITE trial. Methods: In the LITE randomized clinical trial, participants with PAD were randomized to one of three groups for 12 months: home-based high intensity exercise (walking exercise inducing ischemic leg symptoms), home-based low intensity exercise (walking exercise without ischemic leg symptoms) or a control group (no exercise). The primary outcome was 12-month change in six-minute walk test (6MWT) distance. Hospitalizations were ascertained by monthly telephone calls to participants. Results: Of the 305 PAD participants randomized, 291 (95%) participants (mean age: 69, Black race: 59%) were alive at trial ending. Overall, high intensity exercise improved 6MWT compared to low intensity exercise (mean diff: +38.5 m [95% CI: 19.0, 58.1], P &lt; 0.001) and compared to control (mean diff: +43.7 m [95% CI: 23.2, 64.2], P &lt; 0.001). 95 participants had one or more hospitalization during the study period, including 37 (32%) in the high intensity group, 39 (36%) in the low intensity group, and 19 (29%) in the control group (P = 0.64). In the high intensity group, participants hospitalized during the trial had lower baseline 6MWT compared to those not hospitalized [294 meters vs. 349 meters (P = 0.005)]. Among high intensity participants, hospitalization during the trial was associated with less 6MWT improvement at 12-month follow-up (Table). Conclusion: Among people with PAD, hospitalization during an exercise intervention was associated with significantly less improvement in walking performance. Future studies should identify therapies to increase gains in walking performance in patients with PAD hospitalized during exercise interventions.
Abstract 11064: Role of Renin-Angiotensin System Axis in Human Abdominal Aortic Aneurysm
Authors: Vinicius Flora Dugaich, Fabiola Mestriner, Carlos Corsi, Carolina D Avila Mesquita, Daniely Franco Francisco, Jociany Vasconcelos, Cassiana M Mathias Ferreira dos Santos, Lígia C Campos, Ariel Couto, Maria CecÃlia C Jordani, Edwaldo E Joviliano, Paulo Roberto B Evora, Katarzyna Polonis, Maurício S Ribeiro, Christiane Becari
Journal: Circulation (2022)

Introduction: Renin-Angiotensin System (RAS) regulates the cardiovascular system and has been implicated in the development of abdominal aortic aneurysm (AAA). RAS modulates function via balancing the ACE/Chymase/AngII-AT1 receptor and ACE-2/Ang(1-7)-Mas receptor axis. Preferential activation of the ACE/Chymase/AngII-AT1 receptor pathway of the RAS contributes to dysregulation of cardiovascular system and disease while the Ang(1-7)-MasR axis contributes to anti-inflammatory pathways. Therefore, identifying the RAS axis mechanism involved in growth, progression, or the risk of rupture in AAA humans could bring a novel treatment perspective. Hypothesis: We hypothesize that in the AAA, the local RAS is altered such as it favours the ACE/AngII/AT1R axis while decreasing the ACE-2/Ang(1-7)/MasR pathway, with consequent AAA development. Objective: We sought to investigate the expression of RAS components in the AAA human aorta. Methods: Aorta tissue from AAA patients (n=21) was collected during the AAA conventional repair surgery, and aorta control aortas were obtained from organ donors (Control, n=11). Protein expression of renin, chymase, ACE, ACE-2 AT1, AT2, and MAS receptors was analyzed by Western Blotting. Results: Our AAA cohort consisted mostly males (76.6% AAA vs. 63.6% Control, p=0.68), smokers or ex-smokers (90.4% AAA vs. 36.3% Control, p=0.002) and most of them had hypertension(71.4% AAA vs. 36.3% Control, p=0.07). Analysis of protein expression in the AAA group showed that ACE and AT1 receptors were upregulated compared with Control (p=0.05; p=0.02, respectively,), while chymase expression was decreased in AAA compared to the control (p=0.03). Additionally, the AAA group showed downregulation in ACE-2 and AT2 compared with Control (respectively, p=0.01, p=0.03). There was no significant difference in the expression of renin and MAS receptors between groups (p=0.52, p=0.41, respectively,). Conclusions: Our data show that the ACE/AT1R axis was upregulated while ACE-2 and AT2 receptors were downregulated in the AAA aorta. Our results implicate local RAS in AAA development and warrant further studies.
Abstract 12339: Aggressive Additional Treatment Strategies to Eliminate Coronary Artery Aneurysms in Treatment-Resistant Kawasaki Disease
Authors: Yukako Yoshikane, Tatsuki Miyamoto, ATsushi Ogawa, Shinichiro Nagamitsu
Journal: Circulation (2022)

Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery aneurysms (CAAs) especially in treatment-resistant cases. Even with steroid combination therapy, sometimes the fever may persist or recur and requires several additional treatments, which cause CAAs. We reported previously about the scoring systems to predict non-responders to the initial steroid combination therapy. The aim of this study is to prove whether aggressive additional treatment strategies can prevent CAAs in patients at high risk of resistance to initial steroid combination therapy. Methods: The subjects were 39 KD patients with high scores in the scoring systems to predict non-responders to the initial steroid combination therapy*. *Patients who had high scores in all three predictive scoring systems in Japan, and scored 3 points or more in the following scoring system: Kobayashi scores ≥7, 2 points; Egami scores ≥4, 1 point; Number of neutrophils after initial treatment≥ 12000/μL, 2 points* Group 1 (n=26) received additional treatment after recurrent fever (ordinary strategy), Group 2 (n=13) received additional treatment before recurrent fever (aggressive strategy). We compared the incidence of CAAs (including transient dilatation) in each group. Results: In Group 1, there were 15 non-responders (58%) to the initial steroid combination therapy, compared to 0 in Group 2 (p&lt;0.01). All of them had recurrent fever after resolving the fever once. The median day of recurrent fever was day 6 [5.3-7]. In Group 1, there were 5 patients (19%) who had coronary artery dilation greater than z-score &gt;2.5 by treatment resistance, compared to 0 in Group 2 (p&lt;0.01). Conclusions: The aggressive additional treatment strategies (intervention before recurrent fever) prevent CAAs in patients at high risk of resistance to initial steroid combination therapy. Even if the fever is relieved once in the initial treatment, it seems important to prevent recurrent fever around day 7 when histological changes begin in high-risk patients.